TY - JOUR
T1 - BRCA1 haploinsufficiency for replication stress suppression in primary cells
AU - Pathania, Shailja
AU - Bade, Sangeeta
AU - Le Guillou, Morwenna
AU - Burke, Karly
AU - Reed, Rachel
AU - Bowman-Colin, Christian
AU - Su, Ying
AU - Ting, David T.
AU - Polyak, Kornelia
AU - Richardson, Andrea L.
AU - Feunteun, Jean
AU - Garber, Judy E.
AU - Livingston, David M.
N1 - Publisher Copyright:
© 2014Macmillan Publishers Limited. All rights reserved.
PY - 2015/2
Y1 - 2015/2
N2 - BRCA1 - a breast and ovarian cancer suppressor gene - promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed 'conditional' haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.
AB - BRCA1 - a breast and ovarian cancer suppressor gene - promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed 'conditional' haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.
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U2 - 10.1038/ncomms6496
DO - 10.1038/ncomms6496
M3 - Article
C2 - 25400221
AN - SCOPUS:84923274501
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 5496
ER -